Adult Polycystic Kidney Disease: Who Needs Hospital Follow‐Up?

Clinical data from 120 adult patients with genetically undifferentiated polycystic kidney disease who had been followed up for more than 3 months (range 3-172) were reviewed in order to try to identify clinical indicators that might predict deterioration in renal function. They were split into two groups dependent on whether annualized fall in estimated glomerular filtration rate (ΔeGFR mL/min/1.73 m(2) /year) was statistically significant or not. Only 26 patients (22%) had a statistically significantly decreasing ΔeGFR with a median decrease of -2.6 mL/min/1.73 m(2) /year (range -6.2 to -0.7). There was no difference in initial age, gender, or racial distributions between the groups or in initial eGFR. Follow-up was longer (median 86, range 23-172 months vs. 46, range 3-161 months; P = 0.002) and initial blood pressure values tended to be lower (with mean systolic values of 128 vs. 148 mm Hg; P = 0.02) in the group with statistically significant fall in ΔeGFR, but this trend failed to achieve an a priori level of statistical significance. However, the proportion of patients with initial systolic blood pressure ≤ 144 developing a statistically significant fall in ΔeGFR was 0.26 (95% confidence interval = 0.13 to 0.45). No differences were found in initial hemoglobin or cholesterol concentrations. Overall, the annualized rate of decrease in eGFR tended to be greater in those with the higher initial eGFR (P = 0.04), but correlation was poor (rho(2) = 0.04) and failed to achieve an a priori level of statistical significance. No statistically significant correlation was found between ΔeGFR and any other variable. Only those patients with polycystic kidney disease with a statistically significant annualized decrease in eGFR may need to be referred for hospital follow-up in the renal clinic. This simple selection would reduce referrals by 78%.     

Percutaneous Nephrolithotomy in Autosomal Dominant Polycystic Kidney Disease: Is it Different from Percutaneous Nephrolithotomy in Normal Kidney?

Objectives

Nephrolithiasis has been reported in 20-28% of patients, of whom 50% are symptomatic for stone disease and 20% require definite urologic intervention. The management of nephrolithiasis includes oral alkali dissolution therapy, extracorporeal shock wave lithotripsy and surgical treatment. In such patients, percutaneous nephrolithotomy (PNL) as a method of stone treatment has been reported in few cases with limited experience. The aim of this study is to present our experience of PNL in autosomal dominant polycystic kidney disease (ADPKD) and assessing the outcome results.

Material and Methods

From 2002 to 2011, 22 patients (26 renal units) suffering from ADPKD with stone were managed by PNL. Demographic characteristics, operative parameters and postoperative complications were recorded and analysed.

Result

The overall success rate of PNL was 82.1% and PNL with extracorporeal shock wave lithotripsy for clinically significant residual fragments was 92.85% respectively. The hematuria required blood transfusion (n = 9), postoperative fever due to cyst infection (n = 4) and paralytic ileus (n = 3) were recorded.

Conclusion

The PNL in ADPKD PNL is safe and effective but have more postoperative complications such as bleeding requiring transfusions, fever due to cyst infection and paralytic ileus.Key Words: Percutaneous nephrolithotomy, Nephrolithiasis, Autosomal dominant polycystic kidney disease     

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham''s retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research.     

Therapeutic mTOR Inhibition in Autosomal Dominant Polycystic Kidney Disease: What Is the Appropriate Serum Level?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.     

TGF-β/Smad Signaling in Kidney Disease

Chronic progressive kidney diseases typically are characterized by active renal fibrosis and inflammation. Transforming growth factor-β1 (TGF-β1) is a key mediator in the development of renal fibrosis and inflammation. TGF-β1 exerts its biological effects by activating Smad2 and Smad3, which is regulated negatively by an inhibitory Smad7. In the context of fibrosis, although Smad3 is pathogenic, Smad2 and Smad7 are protective. Under disease conditions, Smads also interact with other signaling pathways, such as the mitogen-activated protein kinase and nuclear factor-κB pathways. In contrast to the pathogenic role of active TGF-β1, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Furthermore, recent studies have shown that TGF-β/Smad signaling plays a regulating role in microRNA-mediated renal injury. Thus, targeting TGF-β signaling by gene transfer of either Smad7 or microRNAs into diseased kidneys has been shown to retard progressive renal injury in a number of experimental models. In conclusion, TGF-β/Smad signaling plays a critical role in renal fibrosis and inflammation. Advances in understanding of the mechanisms of TGF-β/Smad signaling in renal fibrosis and inflammation during chronic kidney diseases should provide a better therapeutic strategy to combat kidney diseases.     

Role of Urinary Neutrophil Gelatinase–Associated Lipocalin for Predicting the Severity of Renal Functions in Patients With Autosomal-Dominant Polycystic Kidney Disease

Background

Autosomal-dominant polycystic kidney disease (ADPKD) has a feature of disruption of tubular integrity with increased cellular proliferation and apoptosis. There are several known tubular membrane proteins in the pathogenesis of ADPKD, and one of these proteins is the neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a protein expressed on renal tubular cells of which production is markedly increased in response to harmful stimuli such as ischemia or toxicity.

Chronic Kidney Disease–Induced Vascular Calcification Impairs Bone Metabolism

An association between lower bone mineral density (BMD) and presence of vascular calcification (VC) has been reported in several studies. Chronic kidney disease (CKD) causes detrimental disturbances in the mineral balance, bone turnover, and development of severe VC. Our group has previously demonstrated expression of Wnt inhibitors in calcified arteries of CKD rats. Therefore, we hypothesized that the CKD-induced VC via this pathway signals to bone and induces bone loss. To address this novel hypothesis, we developed a new animal model using isogenic aorta transplantation (ATx). Severely calcified aortas from uremic rats were transplanted into healthy rats (uremic ATx). Transplantation of normal aortas into healthy rats (normal ATx) and age-matched rats (control) served as control groups. Trabecular tissue mineral density, as measured by μCT, was significantly lower in uremic ATx rats compared with both control groups. Uremic ATx rats showed a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog in bone. In addition, we found significant changes in bone mRNA levels of several genes related to extracellular matrix, bone turnover, and Wnt signaling in uremic ATx rats, with no difference between normal ATx and control. The bone histomorphometry analysis showed significant lower osteoid area in uremic ATx compared with normal ATx along with a trend toward fewer osteoblasts as well as more osteoclasts in the erosion lacunae. Uremic ATx and normal ATx had similar trabecular number and thickness. The bone formation rate did not differ between the three groups. Plasma biochemistry, including sclerostin, kidney, and mineral parameters, were similar between all three groups. ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin. In conclusion, the presence of VC lowers BMD, impairs bone metabolism, and affects several pathways in bone. The present results prove the existence of a vasculature to bone tissue cross-talk. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Is There a Role for Bisphosphonates in Chronic Kidney Disease?

Patients with stage 5 chronic kidney disease (CKD) including those on dialysis can and do develop osteoporosis. They also develop a wide range of other metabolic bone diseases that may look like osteoporosis when it is defined by either the World Health Organization bone mineral density (BMD) criteria or by the development of fragility fractures. Those dialysis patients with osteoporosis that is due to gonadal hormone deficiency such as postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, or male osteoporosis may benefit from the administration of bisphosphonates (BPs). The challenges lie in the diagnosis of osteoporosis in this population where adynamic, osteomalacic, hyperparathyroid, or aluminum bone disease are also prevalent, with concommitant low BMD and low trauma fractures, but where BPs may be contraindicated. The only secure means to diagnose osteoporosis in this patient population is by quantitative bone histomorphometry demonstrating low trabecular bone volume and disrupted microarchitecture. Once the diagnosis of osteoporosis is established, BPs should be considered for a well-defined brief period of time (e.g., 2-3 years), even though there is no evidence for a fracture reduction benefit in this population. If a BP is chosen there may be a need for dose adjustment or slower infusion rates (for the intravenous formulations), as a greater bone retention may occur for these renally cleared agents. While it is unknown what consequences could develop from increased bone retention in patients with little renal function, data are needed if more bone retention of BP might lead to a greater risk of the development of adynamic bone disease and lower bone strength. More data are needed to define the risks and benefits of BPs in patients with stage 5 CKD.     

Should Hemoglobin be Normalized in Patients with Chronic Kidney Disease?

In the last decade the nephrology community has learned much about the impact of anemia on patients with kidney disease. Therapy of anemia can correct many of the symptoms which seriously compromise patient function. Despite the obvious benefits, controversy continues regarding the optimal target hemoglobin concentration both in patients prior to dialysis and in dialysis populations. In this editorial we review the clinical data that contribute to this controversy and the physiologic concepts underlying the treatment of anemia. Furthermore, we discuss the need to individualize hemoglobin targets for specific patient populations and the importance of early identification and treatment of anemia in patients with kidney disease. The economic impact of normalizing hemoglobin with the use of erythropoietin and intravenous or oral iron has affected clinical practice over the last decade. Current guidelines published by Kidney Disease Outcomes and Quality Initiative (KDOQI), the European Working Group on Anemia Management, and the Canadian Society of Nephrology all recommend target hemoglobin concentrations and thresholds for initiation of therapy and also suggest the need for reevaluation of current targets in light of new evidence. This editorial supports those guidelines and challenges the reader to critically evaluate current practice in the context of the accumulating data and the physiologic principles discussed herein. The therapy of anemia in patients with chronic kidney disease (CKD) is becoming increasingly sophisticated and is an essential component of care in patients with CKD. However, the effects of therapy will be most impressive when accompanied by the optimal care of all hemodynamic and metabolic abnormalities that are associated with CKD.     

Heme Oxygenase-1 as a Target for TGF-β in Kidney Disease

Transforming growth factor-β (TGF-β) is a multifunctional regulatory cytokine that is implicated in a variety of kidney diseases, including diabetic nephropathy and chronic transplant rejection, where it promotes stimulation of the extracellular matrix deposition, cell proliferation, and migration. TGF-β exerts its biological functions largely via its downstream complex signaling molecules, Smad proteins. Paradoxically, TGF-β also is essential for normal homeostasis and suppression of inflammation through mechanisms that are yet to be fully elucidated. One feasible mechanism by which TGF-β may exert its beneficial properties is through induction of heme oxygenase-1 (HO-1). Induction of this redox-sensitive enzyme is known to be cytoprotective through its potent antioxidant, anti-inflammatory, and anti-apoptotic properties in different conditions including several kidney diseases. In this overview, recent advances in our understanding of the role of TGF-β in kidney disease, its molecular regulation of HO-1 expression, and the potential role of HO-1 induction as a therapeutic modality in TGF-β-mediated kidney diseases are highlighted.     

A Protein Kinase A–Independent Pathway Controlling Aquaporin 2 Trafficking as a Possible Cause for the Syndrome of Inappropriate Antidiuresis Associated with Polycystic Kidney Disease 1 Haploinsufficiency

Renal water reabsorption is controlled by arginine vasopressin (AVP), which binds to V2 receptors, resulting in protein kinase A (PKA) activation, phosphorylation of aquaporin 2 (AQP2) at serine 256, and translocation of AQP2 to the plasma membrane. However, AVP also causes dephosphorylation of AQP2 at S261. Recent studies showed that cyclin-dependent kinases (cdks) can phosphorylate AQP2 peptides at S261 in vitro. We investigated the possible role of cdks in the phosphorylation of AQP2 and identified a new PKA-independent pathway regulating AQP2 trafficking. In ex vivo kidney slices and MDCK-AQP2 cells, R-roscovitine, a specific inhibitor of cdks, increased pS256 levels and decreased pS261 levels. The changes in AQP2 phosphorylation status were paralleled by increases in cell surface expression of AQP2 and osmotic water permeability in the absence of forskolin stimulation. R-Roscovitine did not alter cAMP-dependent PKA activity but specifically reduced protein phosphatase 2A (PP2A) expression and activity in MDCK cells. Notably, we found reduced PP2A expression and activity and reduced pS261 levels in Pkd1^+/− mice displaying a syndrome of inappropriate antidiuresis with high levels of pS256, despite unchanged AVP and cAMP. Similar to previous findings in Pkd1^+/− mice, R-roscovitine treatment caused a significant decrease in intracellular calcium in MDCK cells. Our data indicate that reduced activity of PP2A, secondary to reduced intracellular Ca²⁺ levels, promotes AQP2 trafficking independent of the AVP–PKA axis. This pathway may be relevant for explaining pathologic states characterized by inappropriate AVP secretion and positive water balance.In most mammals, regulation of water balance is critically dependent on water intake and excretion, which is under control of the antidiuretic hormone arginine vasopressin (AVP). In the kidney, AVP binds to the V2 vasopressin (V2R) receptor, activating the cAMP/protein kinase A (PKA) signal transduction cascade, promoting the fusion of intracellular vesicles containing aquaporin 2 (AQP2) to the apical plasma membrane, and increasing luminal permeability.^1–3 This translocation is accompanied by AVP-dependent phosphorylation of AQP2 at serine-256 (pS256).Mice in which S256 could not be phosphorylated (AQP2-S256L) develop polyuria and hydronephrosis because of a defect in AQP2 trafficking to the plasma membrane.⁴ Interestingly, it connects to polycystic kidney disease (PKD). Mutations in polycystin-1 (Pkd1^+/−) gene cause PKD, whereas PKD1 haplo-insufficient mice (Pkd1^+/−), showing an inappropriate antidiuresis, display significantly higher levels of pS256 compared with wild-type (WT) littermates; the prominent expression at the apical plasma membrane of collecting duct principal cells, despite normal V2R expression and normal cAMP levels, is associated with unchanged AVP expression in the brain, despite chronic hypo-osmolality.⁵These observations underscore the crucial role of AQP2 phosphorylation at S256 in controlling the cellular distribution and fate of AQP2.^1,6,7 As for many proteins, the function and the trafficking of AQP2 are modulated by a balance of reversible phosphorylation and dephosphorylation. Preventing dephosphorylation of AQP2 with okadaic acid, inhibitor of phosphatase 1 (PP1), inhibitor of phosphatase 2A (PP2A), and inhibitor of phosphatase 2B (PP2B) significantly increased AQP2-pS256.⁸ Proteomic analysis of inner medulla collecting duct identified PP2A as a phosphoprotein isolated from inner medullary collecting duct samples treated with either calyculin-A, a specific PP2A inhibitor, or vasopressin,⁹ suggesting the possible participation of this phosphatase in cellular events triggered by physiologic stimulus, such as vasopressin in renal collecting duct cells.The complexity of AQP2 regulation was further increased by phosphoproteomics studies showing that, other than S256, vasopressin modulates the phosphorylation status of three other sites within the C terminus (S261, S264, and S269). Although vasopressin increases S264 and S269 phosphorylation, it decreases S261 phosphorylation.^9–12 Regarding the potential kinases responsible for the phosphorylation of these sites, c-Jun N-terminal kinase, p38, and cyclin-dependent kinases (cdks) cdk1 and cdk5 can phosphorylate AQP2 peptides at S261 in vitro.^13,14 Here, in the attempt to investigate the potential involvement of cdks in AQP2 regulation, we discovered a new PKA-independent signal transduction pathway regulating AQP2 phosphorylation and localization. We found that selective inhibition of cdks with R-roscovitine is associated with a decrease of intracellular Ca²⁺ levels and a significant downregulation of the phosphatase PP2A activity, resulting in an increase of AQP2 phosphorylation at S256 and targeting to the apical membrane. Physiologically, this novel regulatory mechanism might be of clinical interest, because it better elucidates the molecular bases of pathologic states characterized by disturbances in water balance.     

Treatment of Anemia With Erythropoietin-Stimulating Agents in Kidney Transplant Recipients and Chronic Kidney Disease—Another Drawback of Immunosuppression?

Anemia is more prevalent in allograft recipients compared with glomerular filtration rate (GFR) matched patients with chronic kidney diseases. There is a paucity of data concerning the correction of anemia in the posttransplant period with erythropoietin-stimulating agents (ESA). The aim of this study was to compare the iron status, kidney function, inflammatory state, use of drugs affecting erythropoiesis (immunosuppressants ACEi/ARB) and correction of anemia using ESA in a chronic kidney disease (CKD) population versus kidney transplant recipients. We included 67 patients treated with ESA including 17 after kidney transplantation. CKD Patients with native kidneys were significantly older than allograft recipients (mean age 69 versus 51 years; P < .001, and despite similar serum creatinine and iron parameters showed an estimated lower GFR (19 mL/min versus 23 mL/min; P < .05). Median time of ESA therapy was similar among patients with native kidney CKD versus kidney recipients, but they achieved a significantly higher hemoglobin (11.04 versus 10.36 g/dL; P < .05). There was no difference between patients administered or not a mammalian target of rapamycin antagonist. None of the patients with native kidney CKD received immunosuppressive therapy, but they were prescribed ACEi more often than kidney recipients. The higher degree of anemia in kidney allograft recipient is the most probably attributed to the use of immunosuppressive drugs, despite their better kidney function and comparable iron status. This study suggested that higher doses of ESA should be employed to anemia in kidney transplant recipients.